Transdermal devices for the delivery of biologically active agents have been used for maintaining health and treating therapeutically a wide variety of ailments. For example, analgesics, steroids, etc., have been delivered with such devices. Such transdermal devices include patches in which a biologically active agent is delivered to the body tissue passively without the use of an additional energy source. Many such devices have been described, for example, in U.S. Pat. Nos. 3,598,122, 3,598,123, 4,379,454, 4,286,592, 4,314,557, 4,568,343, and U.S. Publication No. 20030026829, all of which are incorporated herein by reference.
A transdermal patch is typically a small adhesive bandage that contains the drug to be delivered. A simple type of such transdermal patches is an adhesive monolith including a drug-containing reservoir disposed on a backing. The reservoir is typically formed from a pharmaceutically acceptable pressure sensitive adhesive. In some cases, the reservoir can be formed from a non-adhesive material, with the skin-contacting surface having a thin layer of a suitable adhesive. The rate at which the drug is administered to the patient from these patches can vary due to normal person-to-person and skin site-to-skin site variations in the permeability of skin to the drug.
More complex patches can be a multilaminate or can include drug reservoir layers in the patches. Exemplary transdermal drug delivery systems are illustrated by the embodiments shown in FIGS. 1, 2 and 3. As shown in FIG. 1, a transdermal monolithic patch 1 according to this invention has a backing layer 2, a drug reservoir 3 disposed on the backing layer 2, and a peelable (removable) protective layer 5. In the reservoir 3, which can be a layer, at least the skin-contacting surface 4 is an adhesive. The reservoir is a matrix (carrier) that is suitable for carrying the pharmaceutical agent (or drug) for transdermal delivery. The matrix is a structure in which the drug is or can be dissolved. Preferably, the whole matrix, with drugs and other optional ingredients, is a material that has the desired adhesive property. The reservoir 3 can be either a single phase polymeric composition or a multiple phase polymeric composition. In a single phase polymeric composition the drug and all other components are present at concentrations no greater than, and preferably less than, their saturation concentrations in the reservoir 3. This results in a composition in which no undissolved components are present. The reservoir 3 is formed using a pharmaceutically acceptable polymeric material that can provide adhesive property for application to the body surface. In a multiple phase polymeric composition, at least one component, for example, a therapeutic drug, is initially present in amount more than the saturation concentration. In some embodiments, more than one component, e.g., a drug and a permeation enhancer, is present in amounts above saturation concentration. In the embodiment shown in FIG. 1, the adhesive acts as the reservoir and includes a drug.
In the embodiment shown in FIG. 2, the reservoir 3 is formed from a material that does not have adequate adhesive properties to maintain the patch on the skin for the desired period. In this embodiment of a monolithic patch 1, an overlaying adhesive layer 6 is included to attach the reservoir 3 to the skin. The reservoir 3 may be a single phase polymeric composition or a multiple phase polymeric composition as described earlier, except that it may or may not contain an adhesive with adequate adhesive bonding property for skin. The overlaying adhesive layer 6 can also contain the drug and permeation enhancer, as well as other ingredients. In this design, however, the drug in the reservoir 3 would have to pass through the adhesive layer 6 to reach the body surface. The solubility of the adhesive layer may not be suitable for the rate of delivery desired.
In an alternative prior device shown in FIG. 3, an adhesive layer 6 overlays the protective layer 2 and the reservoir 3 so as to adhere to the body surface with the overhanging portion 8 of the adhesive layer 6. A backing layer 10 protects the adhesive overlay layer 6.
Although the transdermal delivery of therapeutic agents has been the subject of intense research and development for over 30 years, only a relatively small number of drug molecules are suitable for transdermal delivery. For effective delivery, a delivery rate that is therapeutically effective is needed. Many factors affect the delivery rate. The thickness and concentration of the drug reservoir and the layers adjacent to the drug reservoir, as well as the rheological properties of the layers are some of these factors.
Often, due to the chemical as well as physical characteristics (e.g., Theological parameters), a system may change over time, e.g., during a period of storage. For example, the matrix formulations typically cold flow over time. The extent of cold flow can be affected by the fluid characteristics of the reservoir matrix, as well as physical forces that may be applied on the device, for example, by the protective pouch pressing on the reservoir. Typically, the drug delivery patches are made by cutting multiple layers simultaneously, resulting in the layers having the same planer size and their edges being flush on the side of the patch. Thus, for typical patch devices like those shown in FIG. 1 to FIG. 3, reservoir material may migrate along the side of the patch. In the cases of FIG. 1 and FIG. 2 the reservoir material may migrate and come into contact with the inside of a protective pouch, which is used for protecting the device and may not be chemically compatible with the drug reservoir. In the case of FIG. 3, the reservoir material may migrate to the adhesive layer 6. The adhesive layer 6 often is permeable to the drug in the reservoir, allowing the drug to diffuse throughout. If the adhesive contains chemicals to which the reservoir is permeable, the chemicals may migrate into the reservoir. Such unintended chemical migration is highly undesirable as it will reduce the concentration of the active agent in the drug reservoir and thus reduce the delivery rate, and may lead to contamination in the drug reservoir. Further, the inside surface of the protective pouch may contain heat seal polymers, which may allow drug migration from the reservoir. In the cases of FIG. 1 and FIG. 2, cold flow might still cause drug loss by diffusion to the heat seal material in the inside of the pouch. What is needed is a multilayer drug delivery system that is more stable overtime, thus ensuring reliable, predictable delivery of the drug, even for systems that may have been stored for a long period of time.